2 SEPARATE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION PROTEINS REGULATE TRANSCRIPTION OF THE SERINE PROTEINASE INHIBITOR-3 GENE IN HEPATIC CELLS

The serine proteinase inhibitor (SPI-3) gene expression is transcripti onally regulated by interleukin (IL)-6 and glucocorticoids in hepatic cells. To identify the transcription factors involved in regulation of the SPI-3 promoter-chloramphenicol acetyltransferase constructs we ov erexpressed Signal Transducer and Activator of Transcription (STAT) pr oteins (STAT1, STAT3, STAT5B, and STAT6) and CAAT enhancer-binding pro tein beta. Specific: signaling pathways were activated by cointroduced receptors for growth hormone, IL-3, IL-4, or chimeric receptors conta ining the cytoplasmic domain of gp130. STAT3 and STAT5B induced transc ription via the SPI-3 promoter. The STAT5B response was substantially enhanced by truncation of the 5'-flanking region from -1021 to -148. T he responsiveness to STAT3 and STAT5B required the STAT binding elemen t at -132 to -124. This element was sufficient to confer regulation on to a heterologous promoter gene construct. In contrast, overexpression of CAAT enhancer-binding protein beta reduced the transcriptional act ivity of the SPI-3 promoter, presumably by interfering with STAT prote in binding to the promoter element. The SPI-3 gene is the first exampl e of an acute phase gene that is responsive to both STAT3 and STAT5B.